Oral immune response to viral infections have not been well- characterized despite the potential importance as an early line of defense. In particular, herpesviruses implicated in HIV related opportunistic malignancies and HIV itself have potential oral mucosal modes of transmission and yet oral immunity against them remains unexplored. This proposal seeks to characterize oral mucosal immune responses in humans to KSHV, EBV and HIV comparing them to the more well defined immune responses against these viruses in the blood. In addition, we will user a non-human primate model of EBV infection to perform detailed analysis to perform detailed analysis of oral mucosal immunity at distinct sites and time points in rhesus macaques exposed to the rhesus lymphocryptovirus (LCV), a herpesvirus that is closely related to EBV. These experiments will compare immunocompetent animals with those immunodeficient through SIV infection. The specific goals of this project are to: 1. establish the targets of the anti-KSHV specific CTL response in KSHV infected individuals, leading to the further characterization of minimal CTL epitopes derived from KSHV. Using similar methods we will identify CTL responses to rhesus LCV, the similar herpesvirus homolog of EBV in rhesus macaques. 2. Compare the magnitude and target specificity of CTL responses to rhesus LCV and SIV in the oral cavity and peripheral blood of SIV naive and SIV-infected rhesus macaques, 3. Define human CTL responses to HIV, EBV and KSHV infection in the oral cavity compared with blood. We will correlate the magnitude, specificity and kinetics of these responses with 1) disease progression and 2) anti-retroviral treatment. The results from these studies will guide the development of vaccination strategies to induce mucosal immunity in the oral cavity against important pathogens in HIV disease.